Despite extensive investigation into its clinical and molecular pathophysiology, there still exists no treatment modality with proven efficacy for patients with sickle cell disease (SCD). However, based on a recently completed Phase I Trial, hydroxyurea (HU), a drug that increases hemoglobin F production, appears to show considerable promise as a prophylactic agent in SCD. Because HbF inhibits the polymerization of sickle hemoglobin (HbS), and since the polymerization process is the primary determinant of the hemolytic and vaso-occlusive severity of SCD, it has generally been assumed that the apparent clinical benefit of HU is linked to the increased circulating HbF levels. However, because HU has a variety of other effects on the sickle erythrocyte (SS RBC), it is our hypothesis that HU's efficacy in SCD is not simply a consequence of an increase in HbF production. Rather, we suggest that a number of the other RBC effects may also be important, and could well act synergistically with HbF, to inhibit HbS polymerization, to reduce the rate of hemolysis, and to ameliorate the course of the clinical illness. In this application, we have proposed to characterize a wide variety of physiological, rheological, and functional parameters of SS RBC before, and then longitudinally during the course of, HU therapy. Our goals are first to identify one or more baseline RBC parameters which might serve as predictors of a positive response to HU, both in terms of a decrease in the frequency of vaso-occlusive events and of a fall in the rate of red cell destruction. To date, no such predictor exists. Because of HU's toxicity and the unknown risks of its long-term administration in this patient population, a predictor would be quite valuable in SCD. We will also try to define the mechanism(s) by which HU exerts its clinical benefit by correlating and/or separating its HbF effect with/from its effects on other RBC parameters. These studies will employ both SS and AA RBC, the latter obtained from patients with one of the myeloproliferative disease. Finally, because HU is a potentially toxic drug with efficacy that remains to be proven, we will continue to examine alternative drugs or compounds that may also have a therapeutic role in SCD.